Figure 1.

Checkpoints for elimination of autoreactive B cells. B-cell receptors in developing B cells are generated by random V(D)J gene recombinations,
resulting in nearly 75% B cells with polyreactivity. A significant portion of polyreactive
specificities are eliminated thought the mechanisms of receptor editing or deletion
at the central tolerance checkpoint. Newly formed B cells, which have escaped negative
selection in the bone marrow, migrate to the periphery and either enter the splenic
red pulp or circulate thought the blood. An additional selection of autoreactive B
cells occurs at the peripheral checkpoint in the spleen as newly emigrants become
mature naïve follicular (FO) B cells. Upon exposure to antigen and additional selection
steps, B cells can form germinal centers (GCs) and differentiate into memory B cells.
Mutations in genes known to result in impaired negative selection at each checkpoint
are indicated. Percentages refer to the frequencies of autoreactive B cells found
in different cell subsets. Relative expression levels of activation-induced deaminase
(AID) are also indicated. Btk, Bruton's tyrosine kinase; CD40L, CD40 ligand; CLPs,
common lymphoid progenitors; IRAK4, interleukin-1 receptor-associated kinase 4; PTPN22,
protein tyrosine phosphatase nonreceptor type 22.